Extensions of previous work and new projects are proposed in four main areas: (1) Studies on preproinsulin structure and of the role of this precursor and related forms in the biosynthesis and segregation of insulin, comparative studies on preproinsulin structure in primitive vertebrates, studies on precursors of other islet hormones, further characterization of insulin mRNA and studies via molecular cloning of the structure and nucleotide sequence both insulin mRNA and th chromosomal genes which code for insulin and/or other islet hormones in various species. (2) Further studies on insulin binding, degradation and action in target tissues such as hepatocytes and hepatocytes and hepatoma cells including studies on the mode of proteolytic cleavage of the hormone, efforts to clarify the relationship between insulin action and the endocytotic processes involved in receptor-mediated insulin uptake and degradation, further efforts to isolate and characterize insulin receptors through the use of specific cross-linking reagents, studies on insulin receptor antibodies and on insulin effects in isolated plasma membrane preparations and other resolved systems. (3) Further studies on the propagation of islet cell tumors in vivo and in vitro and on factors which regulate B cell replication in cultured adult islets of Langerhans, and efforts to develop endocrine cell lines from human and animal islet tumors. (4) Studies on isolated islet cells from rats and mice with emphasis on the development of methods for separating islet cells subpopulations by means of fluorescence-activated cell sorting. Further studies on the characterization of islet cell antigenic components and on the pathogenetic significance of the circulating non-species specific islet cell antibodies that occur early in the course of insulin-dependent diabetes.